Comparative Analysis of Apoptosis and Inflammation Genes of Mice and Humans

Apoptosis (programmed cell death) plays important roles in many facets of normal mammalian physiology. Host-pathogen interactions have provided evolutionary pressure for apoptosis as a defense mechanism against viruses and microbes, sometimes linking apoptosis mechanisms with inflammatory responses through NFκB induction. Proteins involved in apoptosis and NFκB induction commonly contain evolutionarily conserved domains that can serve as signatures for identification by bioinformatics methods. Using a combination of public (NCBI) and private (RIKEN) databases, we compared the repertoire of apoptosis and NFκB-inducing genes in humans and mice from cDNA/EST/genomic data, focusing on the following domain families: (1) Caspase proteases; (2) Caspase recruitment domains (CARD); (3) Death Domains (DD); (4) Death Effector Domains (DED); (5) BIR domains of Inhibitor of Apoptosis Proteins (IAPs); (6) Bcl-2 homology (BH) domains of Bcl-2 family proteins; (7) Tumor Necrosis Factor (TNF)-family ligands; (8) TNF receptors (TNFR); (9) TIR domains; (10) PAAD (PYRIN; PYD, DAPIN); (11) nucleotide-binding NACHT domains; (12) TRAFs; (13) Hsp70-binding BAG domains; (14) endonuclease-associated CIDE domains; and (15) miscellaneous additional proteins. After excluding redundancy due to alternative splice forms, sequencing errors, and other considerations, we identified cDNAs derived from a total of 227 human genes among these domain families. Orthologous murine genes were found for 219 (96%); in addition, several unique murine genes were found, which appear not to have human orthologs. This mismatch may be due to the still fragmentary information about the mouse genome or genuine differences between mouse and human repertoires of apoptotic genes. With this caveat, we discuss similarities and differences in human and murine genes from these domain families.     

Nuclear organization and morphology of cholinergic, putative catecholaminergic and serotonergic neurons in the brain of the Cape porcupine (Hystrix africaeaustralis): increased brain size does not lead to increased organizational complexity

The distribution, morphology and nuclear organization of the cholinergic, putative catecholaminergic and serotonergic systems within the brain of the Cape porcupine (Hystrix africaeaustralis) were identified following immunohistochemistry for choline acetyltransferase, tyrosine hydroxylase and serotonin. The aim of the present study was to investigate possible differences in the complement of nuclear subdivisions of these systems in the Cape porcupine in comparison with previous studies of these systems in other rodents. The Cape porcupine is the largest rodent in which these systems have been examined and has an adult body mass of 10-24kg and an average brain mass of approximately 37g, around 15 times larger than the laboratory rat. The Cape porcupines were taken from the wild and while these differences, especially that of mass, may lead to the prediction of a significant difference in the nuclear organization or number within these systems, all the nuclei observed in all three systems in the laboratory rat and in other rodents had direct homologues in the brain of the Cape porcupine. Moreover, there were no additional nuclei in the brain of the Cape porcupine that are not found in the laboratory rat or other rodents studied and vice versa. It is noted that the medial septal nucleus of the Cape porcupine appeared qualitatively to have a reduced number of neurons in comparison to the laboratory rat and other rodents. The locus coeruleus of the laboratory rat differs in location to that observed for the Cape porcupine and several other rodent species. The Cape porcupine is distantly related to the laboratory rat, but still a member of the order Rodentia; thus, changes in the organization of these systems appears to demonstrate a form of constraint related to the phylogenetic level of the order.     

Perception of dental fluorosis amongst Ethiopian children and their mothers

This study was conducted in three Ethiopian Rift Valley villages known for endemic fluorosis. Three-hundred-and-six adolescents (12-15 years) and 233 mothers participated. The aim was to study dental fluorosis in the youngsters and to assess the extent of agreement between clinical and self-rated discoloration and pitting of teeth, and also the level at which dental fluorosis is perceived as a problem both by children and their mothers. The children (154 M and 152 F) gave a simple self-assessment of tooth-color and quality of their teeth, and were subsequently examined for dental fluorosis. Finally, four color photographs of teeth with dental fluorosis (TF-scores 2, 3, 5, and 7) were used as references during a structured oral interview of the children, as well as their mothers. At TF score &#83 2, the prevalence of dental fluorosis on maxillary central incisors was 72% and 37% at TF score &#83 4. The mean TF score was significantly higher among boys than among girls of unemployed fathers compared to children of employed fathers. The likelihood of reporting problems with dental appearance increased with increasing individual TF scores. The child/mother pairs found teeth with TF scores 2 and 3 esthetically acceptable, while teeth with TF scores 5 and 7 were considered unacceptable. Mothers were more critical of severe fluorosis than were their children.     

OSU-6162, a Sigma1R Ligand in Low Doses,Can Further Increase the Effects of Cocaine Self-Administration on Accumbal D2R Heteroreceptor Complexes

Neurotoxicity Research - Cocaine was previously shown to act at the Sigma1R which is a target for counteracting cocaine actions. It therefore becomes of interest to test if the monoamine stabilizer...     

High-throughput interrogation of PIK3CA,PTEN, KRAS,FBXW7 and TP53 mutations in primary endometrial carcinoma

ObjectiveEndometrial cancer patients may benefit from systemic adjuvant chemotherapy, alone or in combination with targeted therapies. Prognostic and predictive markers are needed, however, to identify patients amenable for these therapies.MethodsPrimary endometrial tumors were genotyped for > 100 hot spot mutations in genes potentially acting as prognostic or predictive markers. Mutations were correlated with tumor characteristics in a discovery cohort, replicated in independent cohorts and finally, confirmed in the overall population (n = 1063).ResultsPIK3CA, PTEN and KRAS mutations were most frequently detected, respectively in 172 (16.2%), 164 (15.4%) and 161 (15.1%) tumors. Binary logistic regression revealed that PIK3CA mutations were more common in high-grade tumors (OR = 2.03; P = 0.001 for grade 2 and OR = 1.89; P = 0.012 for grade 3 compared to grade 1), whereas a positive TP53 status correlated with type II tumors (OR = 11.92; P < 0.001) and PTEN mutations with type I tumors (OR = 19.58; P = 0.003). Conversely, FBXW7 mutations correlated with positive lymph nodes (OR = 3.38; P = 0.045). When assessing the effects of individual hot spot mutations, the H1047R mutation in PIK3CA correlated with high tumor grade and reduced relapse-free survival (HR = 2.18; P = 0.028).ConclusionsMutations in PIK3CA, TP53, PTEN and FBXW7 correlate with high tumor grade, endometrial cancer type and lymph node status, whereas PIK3CA H1047R mutations serve as prognostic markers for relapse-free survival in endometrial cancer patients.     

Experiences with nutrition-related information during antenatal care of pregnant women of different ethnic backgrounds residing in the area of Oslo,Norway

Objectiveto explore experiences with nutrition-related information during routine antenatal care among women of different ethnical backgrounds.Designindividual interviews with seventeen participants were conducted twice during pregnancy. Data collection and analysis were inspired by an interpretative phenomenological approach.Settingparticipants were purposively recruited at eight Mother and Child Health Centres in the area of Oslo, Norway, where they received antenatal care.Participantsparticipants had either immigrant backgrounds from African and Asian countries (n=12) or were ethnic Norwegian (n=5). Participants were pregnant with their first child and had a pre-pregnancy Body Mass Index above 25 kg/m².Findingsparticipants experienced that they were provided with little nutrition-related information in antenatal care. The information was perceived as presented in very general terms and focused on food safety. Weight management and the long-term prevention of diet-related chronic diseases had hardly been discussed. Participants with immigrant backgrounds appeared to be confused about information given by the midwife which was incongruent with their original food culture. The participants were actively seeking for nutrition-related information and had to navigate between various sources of information.Conclusionsthe midwife is considered a trustworthy source of nutrition-related information. Therefore, antenatal care may have considerable potential to promote a healthy diet to pregnant women. Findings suggest that nutrition communication in antenatal care should be more tailored towards women's dietary habits and cultural background, nutritional knowledge as well as level of nutrition literacy.     

Simultaneous dual-radionuclide myocardial perfusion imaging with a solid-state dedicated cardiac camera

Purpose

We compared simultaneous dual-radionuclide (DR) stress and rest myocardial perfusion imaging (MPI) with a novel solid-state cardiac camera and a conventional SPECT camera with separate stress and rest acquisitions.

Methods

Of 27 consecutive patients recruited, 24 (64.5±11.8 years of age, 16 men) were injected with 74 MBq of ²⁰¹Tl (rest) and 250 MBq ^99mTc-MIBI (stress). Conventional MPI acquisition times for stress and rest are 21 min and 16 min, respectively. Rest ²⁰¹Tl for 6 min and simultaneous DR 15-min list mode gated scans were performed on a D-SPECT cardiac scanner. In 11 patients DR D-SPECT was performed first and in 13 patients conventional stress ^99mTc-MIBI SPECT imaging was performed followed by DR D-SPECT. The DR D-SPECT data were processed using a spill-over and scatter correction method. DR D-SPECT images were compared with rest ²⁰¹Tl D-SPECT and with conventional SPECT images by visual analysis employing the 17-segment model and a five-point scale (0 normal, 4 absent) to calculate the summed stress and rest scores. Image quality was assessed on a four-point scale (1 poor, 4 very good) and gut activity was assessed on a four-point scale (0 none, 3 high).

Results

Conventional MPI studies were abnormal at stress in 17 patients and at rest in 9 patients. In the 17 abnormal stress studies DR D-SPECT MPI showed 113 abnormal segments and conventional MPI showed 93 abnormal segments. In the nine abnormal rest studies DR D-SPECT showed 45 abnormal segments and conventional MPI showed 48 abnormal segments. The summed stress and rest scores on conventional SPECT and DR D-SPECT were highly correlated (r=0.9790 and 0.9694, respectively). The summed scores of rest ²⁰¹Tl D-SPECT and DR-DSPECT were also highly correlated (r=0.9968, p<0.0001 for all). In six patients stress perfusion defects were significantly larger on stress DR D-SPECT images, and five of these patients were imaged earlier by D-SPECT than by conventional SPECT.

Conclusion

Fast and high-quality simultaneous DR MPI is feasible with D-SPECT in a single imaging session with comparable diagnostic performance and image quality to conventional SPECT and to a separate rest ²⁰¹Tl D-SPECT acquisition.     

Radiopharmaceuticals for positron emission tomography investigations of Alzheimer’s disease

Alzheimer’s disease (AD) is a common degenerative neurological disease that is an increasing medical, economical, and social problem. There is evidence that a long “asymptomatic” phase of the disease exists where functional changes in the brain are present, but structural imaging for instance with magnetic resonance imaging remains normal. Positron emission tomography (PET) is one of the tools by which it is possible to explore changes in cerebral blood flow and metabolism and the functioning of different neurotransmitter systems. More recently, investigation of protein aggregations such as amyloid deposits or neurofibrillary tangles containing tau-protein has become possible. The purpose of this paper is to review the current knowledge on various ¹⁸F- and ¹¹C-labelled PET tracers that could be used to study the pathophysiology of AD, to be used in the early or differential diagnosis or to be used in development of treatment and in monitoring of treatment effects.     

Efficacy and safety of gadodiamide (Gd-DTPA-BMA) in renal 3D-magnetic resonance angiography (MRA): a phase II study

PURPOSE: To determine the most efficacious dose of gadodiamide for three-dimensional (3D) contrast-enhanced (CE) magnetic resonance angiography (MRA) of the renal arteries on a patient level based on the sensitivity in detecting the main hemodynamically relevant (> or =50% or occlusion) renal artery stenosis (RAS) using intra-arterial digital subtraction angiography (IA DSA) as the gold standard. MATERIALS AND METHODS: This prospective, randomized, double-blind, parallel-group, multicenter study included 273 patients referred to IA DSA for suspected RAS. Patients underwent 3D CE MRA after injection of 0.01, 0.05, 0.1, or 0.2mmol/kg of body weight gadodiamide (0.5mmol/ml). The images were assessed for location and degree of RAS by independent blinded readers (MRA: three readers, IA DSA: one reader). Hypothesis testing for a significant trend in sensitivity across dose groups was based on the one-sided Cochran-Armitage style trend test for each independent MRA reader. RESULTS: The lowest dose group (0.01mmol/kg) proved non-efficacious in detecting hemodynamically relevant (i.e., > or =50% or occlusion) RAS. A statistically significant dose trend (p<0.001) was shown for each of the three independent readers. Depending on reader, the sensitivity obtained with 0.05, 0.1, and 0.2mmol/kg was 63.9-86.1%, 75.8-91.4% and 80.6-90.6%, the specificity was 66.7-73.9%, 59.3-75.0%, and 59.3-75.0% and accuracy was 67.8-78.9%, 75.4-77.4%, and 76.3-81.0%, for the three dose groups, respectively. There were eight non-severe adverse events (AEs). Three serious AEs occurring in one patient were judged not related to gadodiamide by the on-site investigator. CONCLUSION: A significant dose trend between the four doses examined was observed. The lowest dose (0.01mmol/kg) differed significantly from those of the other three doses. Based on the analysis of the primary and secondary endpoints, 0.1mmol/kg gadodiamide appears to be the most suitable dose in diagnosing hemodynamically relevant RAS. The present study also demonstrated gadodiamide to be safe and well tolerated.